Monobactam organic compounds for the treatment of bacterial infections

Abstract

This invention pertains generally to antibacterial compounds of Formula I, as further described herein, and pharmaceutically acceptable salts and formulations thereof. In certain aspects, the invention pertains to methods of using such compounds to treat infections such as those caused by Gram-negative bacteria.

1 . A method to treat a Gram-negative bacterial infection, which comprises administering to a subject in need of such treatment a compound of Formula (IA): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 Z is CH; 
 the group —O—CR 1 R 2 R 3  is selected from 
 
       
         
           
           
               
               
           
         
         Het is selected from 
       
       
         
           
           
               
               
           
         
       
       and 
       wherein the bacterial infection is nosocomial pneumonia, an intraabdominal infection, or a urinary tract infection. 
     
     
         2 .- 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the compound is selected from:
 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof;   1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(guanidinomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof; and   (S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-(piperidin-4-yl)carbamimidoyl)-phenoxy)propanoic acid, or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The method of  claim 1 , wherein the compound is:
 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3-yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The method of  claim 1 , wherein the compound is:
 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(guanidinomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.   
     
     
         21 . The method of  claim 1 , wherein the compound is:
 (S)-2-(((Z)-(2-(((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-3-(4-(N-(piperidin-4-yl)carbamimidoyl)-phenoxy)propanoic acid, or a pharmaceutically acceptable salt thereof.   
     
     
         22 . The method of  claim 1 , wherein the bacterial infection is nosocomial pneumonia. 
     
     
         23 . The method of  claim 1 , wherein the bacterial infection is an intraabdominal infection. 
     
     
         24 . The method of  claim 1 , wherein the bacterial infection is a urinary tract infection. 
     
     
         25 . The method of  claim 1 , wherein the bacterial infection is caused by a species of Enterobacteriaceae.